Background

Additional safe and efficacious vaccines are needed to control the COVID-19 pandemic. We aimed to analyse the efficacy and safety of the CVnCoV SARS-CoV-2 mRNA vaccine candidate.

Methods

HERALD is a randomised, observer-blinded, placebo-controlled, phase 2b/3 clinical trial conducted in 47 centres in ten countries in Europe and Latin America. By use of an interactive web response system and stratification by country and age group (18–60 years and ≥61 years), adults with no history of virologically confirmed COVID-19 were randomly assigned (1:1) to receive intramuscularly either two 0·6 mL doses of CVnCoV containing 12 μg of mRNA or two 0·6 mL doses of 0·9% NaCl (placebo) on days 1 and 29. The primary efficacy endpoint was the occurrence of a first episode of virologically confirmed symptomatic COVID-19 of any severity and caused by any strain from 15 days after the second dose. For the primary endpoint, the trial was considered successful if the lower limit of the CI was greater than 30%. Key secondary endpoints were the occurrence of a first episode of virologically confirmed moderate-to-severe COVID-19, severe COVID-19, and COVID-19 of any severity by age group. Primary safety outcomes were solicited local and systemic adverse events within 7 days after each dose and unsolicited adverse events within 28 days after each dose in phase 2b participants, and serious adverse events and adverse events of special interest up to 1 year after the second dose in phase 2b and phase 3 participants. Here, we report data up to June 18, 2021. The study is registered at ClinicalTrials.gov, NCT04652102, and EudraCT, 2020–003998–22, and is ongoing.

Findings

Between Dec 11, 2020, and April 12, 2021, 39 680 participants were enrolled and randomly assigned to receive either CVnCoV (n=19 846) or placebo (n=19 834), of whom 19 783 received at least one dose of CVnCoV and 19 746 received at least one dose of placebo. After a mean observation period of 48·2 days (SE 0·2), 83 cases of COVID-19 occurred in the CVnCoV group (n=12 851) in 1735·29 person-years and 145 cases occurred in the placebo group (n=12 211) in 1569·87 person-years, resulting in an overall vaccine efficacy against symptomatic COVID-19 of 48·2% (95·826% CI 31·0–61·4; p=0·016). Vaccine efficacy against moderate-to-severe COVID-19 was 70·7% (95% CI 42·5–86·1; CVnCoV 12 cases in 1735·29 person-years, placebo 37 cases in 1569·87 person-years). In participants aged 18–60 years, vaccine efficacy against symptomatic disease was 52·5% (95% CI 36·2–64·8; CVnCoV 71 cases in 1591·47 person-years, placebo, 136 cases in 1449·23 person-years). Too few cases occurred in participants aged 61 years or older (CVnCoV 12, placebo nine) to allow meaningful assessment of vaccine efficacy. Solicited adverse events, which were mostly systemic, were more common in CVnCoV recipients (1933 [96·5%] of 2003) than in placebo recipients (1344 [67·9%] of 1978), with 542 (27·1%) CVnCoV recipients and 61 (3·1%) placebo recipients reporting grade 3 solicited adverse events. The most frequently reported local reaction after any dose in the CVnCoV group was injection-site pain (1678 [83·6%] of 2007), with 22 grade 3 reactions, and the most frequently reported systematic reactions were fatigue (1603 [80·0%] of 2003) and headache (1541 [76·9%] of 2003). 82 (0·4%) of 19 783 CVnCoV recipients reported 100 serious adverse events and 66 (0·3%) of 19 746 placebo recipients reported 76 serious adverse events. Eight serious adverse events in five CVnCoV recipients and two serious adverse events in two placebo recipients were considered vaccination-related. None of the fatal serious adverse events reported (eight in the CVnCoV group and six in the placebo group) were considered to be related to study vaccination. Adverse events of special interest were reported for 38 (0·2%) participants in the CVnCoV group and 31 (0·2%) participants in the placebo group. These events were considered to be related to the trial vaccine for 14 (<0·1%) participants in the CVnCoV group and for five (<0·1%) participants in the placebo group.

Interpretation

CVnCoV was efficacious in the prevention of COVID-19 of any severity and had an acceptable safety profile. Taking into account the changing environment, including the emergence of SARS-CoV-2 variants, and timelines for further development, the decision has been made to cease activities on the CVnCoV candidate and to focus efforts on the development of next-generation vaccine candidates.

Funding

German Federal Ministry of Education and Research and CureVac.

中文翻译：

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CVnCoV SARS-CoV-2 mRNA 候选疫苗在欧洲和拉丁美洲 (HERALD) 十个国家的疗效和安全性：一项随机、观察者盲、安慰剂对照的 2b/3 期试验

背景

需要更多安全有效的疫苗来控制 COVID-19 大流行。我们旨在分析 CVnCoV SARS-CoV-2 mRNA 候选疫苗的有效性和安全性。

方法

HERALD 是一项随机、观察者盲、安慰剂对照的 2b/3 期临床试验，在欧洲和拉丁美洲 10 个国家的 47 个中心进行。通过使用交互式网络响应系统并按国家和年龄组（18-60 岁和 ≥61 岁）进行分层，没有病毒学证实的 COVID-19 病史的成年人被随机分配（1:1）接受肌肉注射两种 0 ·在第 1 天和第 29 天服用 6 mL 剂量的 CVnCoV，其中含有 12 μg mRNA 或两次 0·6 mL 剂量的 0·9% NaCl（安慰剂）。主要疗效终点是首次出现经病毒学证实的症状性 COVID-任何严重程度的 19 例，由第二剂后 15 天的任何应变引起。对于主要终点，如果 CI 的下限大于 30%，则认为试验成功。关键的次要终点是按年龄组分列的病毒学证实的中度至重度 COVID-19、重度 COVID-19 和任何严重程度的 COVID-19 的首发事件。主要安全性结局是在 2b 期参与者中，每次给药后 7 天内出现局部和全身性不良事件，每次给药后 28 天内出现未经请求的不良事件，以及在第二次给药后长达 1 年的严重不良事件和特别关注的不良事件。阶段 2b 和阶段 3 参与者。在这里，我们报告截至 2021 年 6 月 18 日的数据。该研究已在 ClinicalTrials.gov 注册，NCT04652102 和 EudraCT，2020-003998-22，并且正在进行中。主要安全性结局是在 2b 期参与者中，每次给药后 7 天内出现局部和全身性不良事件，每次给药后 28 天内出现未经请求的不良事件，以及在第二次给药后长达 1 年的严重不良事件和特别关注的不良事件。阶段 2b 和阶段 3 参与者。在这里，我们报告截至 2021 年 6 月 18 日的数据。该研究已在 ClinicalTrials.gov 注册，NCT04652102 和 EudraCT，2020-003998-22，并且正在进行中。主要安全性结局是在 2b 期参与者中，每次给药后 7 天内出现局部和全身性不良事件，每次给药后 28 天内出现未经请求的不良事件，以及在第二次给药后长达 1 年的严重不良事件和特别关注的不良事件。阶段 2b 和阶段 3 参与者。在这里，我们报告截至 2021 年 6 月 18 日的数据。该研究已在 ClinicalTrials.gov 注册，NCT04652102 和 EudraCT，2020-003998-22，并且正在进行中。

发现

在 2020 年 12 月 11 日至 2021 年 4 月 12 日期间，39 680 名参与者被招募并随机分配接受 CVnCoV（n=19 846）或安慰剂（n=19 834），其中 19 783 人接受了至少一剂 CVnCoV 19 746 人接受了至少一剂安慰剂。在 48·2 天（SE 0·2）的平均观察期后，1735·29 人年中 CVnCoV 组（n=12 851）发生了 83 例 COVID-19，安慰剂组发生了 145 例（ n=12211）在 1569·87 人年中，导致针对症状性 COVID-19 的总体疫苗效力为 48·2%（95·826% CI 31·0–61·4；p=0·016）。疫苗对中度至重度 COVID-19 的有效性为 70·7%（95% CI 42·5–86·1；CVnCoV 12 例，1735·29 人年，安慰剂 37 例，1569·87 人年） . 在 18-60 岁的参与者中，疫苗对症状性疾病的有效性为 52·5%（95% CI 36·2–64·8；CVnCoV 71 例，1591·47 人年，安慰剂，136 例，1449·23 人年）。61 岁或以上的参与者（CVnCoV 12，安慰剂 9）发生的病例太少，无法对疫苗功效进行有意义的评估。CVnCoV 接受者（1933 年 [96·5%] of 2003）比安慰剂接受者（1978 年 1344 例 [67·9%]）更常见，其中大部分是全身性的不良事件，其中 542 例（27·1%）报告 3 级的 CVnCoV 接受者和 61 名 (3·1%) 安慰剂接受者请求的不良事件。CVnCoV 组任何剂量后最常报告的局部反应是注射部位疼痛（1678 [83·6%] of 2007），有 22 个 3 级反应，最常报告的全身反应是疲劳（1603 [80· 2003 年的 0%]）和头痛（2003 年的 1541 [76·9%]）。19 783 名 CVnCoV 接受者中有 82 名（0·4%）报告了 100 起严重不良事件，19 746 名安慰剂接受者中有 66 名（0·3%）报告了 76 起严重不良事件。5 名 CVnCoV 接受者中的 8 起严重不良事件和 2 名安慰剂接受者中的 2 起严重不良事件被认为与疫苗接种相关。报告的致命严重不良事件（CVnCoV 组 8 例和安慰剂组 6 例）均不被认为与研究疫苗接种有关。CVnCoV 组 38 名 (0·2%) 参与者和安慰剂组 31 名 (0·2%) 参与者报告了特别关注的不良事件。这些事件被认为与 CVnCoV 组 14 名 (<0·1%) 参与者和安慰剂组 5 名 (<0·1%) 参与者的试验疫苗有关。

解释

CVnCoV 可有效预防任何严重程度的 COVID-19，并且具有可接受的安全性。考虑到不断变化的环境，包括 SARS-CoV-2 变体的出现以及进一步开发的时间表，已决定停止对 CVnCoV 候选疫苗的活动，并将重点放在下一代候选疫苗的开发上。

资金

德国联邦教育与研究部和 CureVac。